The broad purpose of this program-project is to show that advances AAV-based gene therapy enable stable, long-term suppression of HIV-1 replication. Our immediate goal is to stably suppress an ongoing SHIV-infection in rhesus macaques, using specific combinations of antiviral proteins delivered by self-complementary AAV vectors. Any effective therapy for HIV-1 infection has to solve the problem of viral escape. This project addresses the problem of viral escape from a cocktail of antibodies iteratively, by rapidly identifying viral escape pathways and adjusting these cocktails so that these pathways are blocked. We are aided in this effort by a variant of CD4-Ig, fused to a 14-amino-acid peptide that closely mimics a high-affinity binding region of CCR5. This enhanced CD4-Ig (